CN114573473A - Preparation method of (R) -alpha-aryl alanine ester derivative - Google Patents
Preparation method of (R) -alpha-aryl alanine ester derivative Download PDFInfo
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- CN114573473A CN114573473A CN202210206296.7A CN202210206296A CN114573473A CN 114573473 A CN114573473 A CN 114573473A CN 202210206296 A CN202210206296 A CN 202210206296A CN 114573473 A CN114573473 A CN 114573473A
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- alpha
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- 235000004279 alanine Nutrition 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 75
- 239000002904 solvent Substances 0.000 claims abstract description 63
- 239000003054 catalyst Substances 0.000 claims abstract description 60
- 238000004821 distillation Methods 0.000 claims abstract description 50
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 49
- 239000001257 hydrogen Substances 0.000 claims abstract description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 49
- 238000001035 drying Methods 0.000 claims abstract description 25
- 239000012074 organic phase Substances 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000002148 esters Chemical class 0.000 claims abstract description 14
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 114
- 239000003446 ligand Substances 0.000 claims description 35
- 239000012300 argon atmosphere Substances 0.000 claims description 22
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- -1 aryl alanine ester Chemical class 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- XXZOEDQFGXTEAD-UHFFFAOYSA-N 1,2-bis(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC=CC=C1C(F)(F)F XXZOEDQFGXTEAD-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 2
- 229930007927 cymene Natural products 0.000 claims description 2
- 125000005394 methallyl group Chemical group 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 48
- 239000010948 rhodium Substances 0.000 description 29
- 229910052786 argon Inorganic materials 0.000 description 24
- 150000004696 coordination complex Chemical class 0.000 description 23
- 239000012298 atmosphere Substances 0.000 description 20
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 5
- 238000011049 filling Methods 0.000 description 3
- HTCSFFGLRQDZDE-SECBINFHSA-N (2r)-2-azaniumyl-2-phenylpropanoate Chemical compound OC(=O)[C@@](N)(C)C1=CC=CC=C1 HTCSFFGLRQDZDE-SECBINFHSA-N 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001371 alpha-amino acids Chemical class 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- 229950008325 levothyroxine Drugs 0.000 description 2
- IKGHIFGXPVLPFD-LLVKDONJSA-N methyl (2r)-2-acetamido-3-phenylpropanoate Chemical compound COC(=O)[C@H](NC(C)=O)CC1=CC=CC=C1 IKGHIFGXPVLPFD-LLVKDONJSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 2
- VUTUHLLWFPRWMT-QMDOQEJBSA-M (1z,5z)-cycloocta-1,5-diene;rhodium;trifluoromethanesulfonate Chemical compound [Rh].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1.[O-]S(=O)(=O)C(F)(F)F VUTUHLLWFPRWMT-QMDOQEJBSA-M 0.000 description 1
- QKZWXPLBVCKXNQ-UHFFFAOYSA-N (2-methoxyphenyl)-[2-[(2-methoxyphenyl)-phenylphosphanyl]ethyl]-phenylphosphane Chemical compound COC1=CC=CC=C1P(C=1C=CC=CC=1)CCP(C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-UHFFFAOYSA-N 0.000 description 1
- VSITVIXKCHXRCK-UHFFFAOYSA-N 2h-1,2-benzoxaphosphinine Chemical compound C1=CC=C2OPC=CC2=C1 VSITVIXKCHXRCK-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000005610 enamide group Chemical group 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 150000003283 rhodium Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- B01J31/22—Organic complexes
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2495—Ligands comprising a phosphine-P atom and one or more further complexing phosphorus atoms covered by groups B01J31/1845 - B01J31/1885, e.g. phosphine/phosphinate or phospholyl/phosphonate ligands
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
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Abstract
The invention discloses aA process for preparing (R) -alpha-arylalanine ester derivative by adding alpha-dehydroarylalanine ester derivative and catalyst [ Rh ] to high-pressure reactor]/L*And a solvent B, carrying out asymmetric hydrogenation reaction at 10-80 ℃ and under the hydrogen pressure of 0.1-6.0 MPa, reacting for 1-24 hours, carrying out reduced pressure distillation to recover the solvent B, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, and carrying out reduced pressure distillation to recover the solvent to obtain the (R) -alpha-aryl alanine ester derivative. The method has the advantages of low catalyst consumption (TON up to 100,000), excellent enantioselectivity (ee value is generally more than 99%), wide substrate applicability and the like, and has the advantages of easily obtained raw materials, simple operation, mild reaction conditions, easy industrialization, accordance with the requirements of green chemistry, great implementation value and social and economic benefits.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a (R) -alpha-aryl alanine ester derivative.
Background
Chiral alpha-amino acids have a wide range of applications in the fields of pharmacy, biology and synthetic chemistry, and their importance is self-evident. Among a plurality of chiral alpha-amino acids, the chiral alpha-aryl alanine is extremely widely distributed, and the body shadow of the chiral alpha-aryl alanine can be found in drug molecules, food additives and the like. Such as Levothyroxine (Levothyroxine) for the treatment of hypothyroidism; ADEP4 capable of resisting multi-drug resistant germ infection, beta 2 receptor antagonist CPD-15A5, spectral anticancer agent LY355703, sweetener Aspartame (Aspartame), and the like.
As such, their synthesis methods are also receiving much attention. The synthesis of chiral alpha-aryl alanine is mainly based on the corresponding asymmetric hydrogenation. In 1972, Kagan reported the first asymmetric hydrogenation of enamides (h.b. Kagan, j.am. chem. soc.,1972,94,6429.), which system used rhodium complexes of DIOP to give N-acetyl protected α -phenylalanine at 72% ee, after which the ene acid derivatives were extensively studied make internal disorder or usurp as an important hydrogenation substrate, with a series of very important results. In 2002, Knowles (w.s.knowles, angelw.chem., int.ed.,2002,41,1998-2007.) involved in asymmetric hydrogenation of α -phenylalanine using a DIPAMP/Rh catalytic system, successfully prepared L-DOPA (97.5% ee) with high optical purity, which was thus awarded for nobel chemical prize in 2001, which was still the mainstream method for producing L-DOPA.
Then, ligands for asymmetric hydrogenation of α -dehydroarylalanine derivatives have emerged as spring shoots after rain, and excellent effects have been obtained, such as the ferrocene skeleton ligand IndoFerroPhos developed in the kupffer topic group (x. — p. hu, Tetrahedron lett.,2020,61, 151860), which can give high yields of (R) - α -arylalanine ester derivatives, but the ee value is only 97% at the highest and the applicability to heterocyclic substrates is poor; the benzoxaphosphine ligand BABIPhos developed by the Thomujin project group (W.J.Tang, org.Lett.,2018,20,1725-1729.) can obtain the (R) -alpha-aryl alanine ester derivative with the ee value of 99%, but the catalyst TON value is only 100; also, the mannitol-derivatized ferrocene-skeleton cyclic phosphine ligands developed by professor Zhang, org.Lett.,2002,4,4471-4474 have the above-mentioned problems.
In 2021, CN112824423A discloses a chiral ferrocenylphosphine-indolylaminophosphine ligand, which can efficiently catalyze and synthesize alpha-dehydroamino acid ester with high optical purity, wherein TON can reach 10000, but the enantioselectivity is 96% ee at most. Although the preparation of (R) -alpha-aryl alanine ester derivatives by asymmetric hydrogenation technology has been developed, the reported catalyst still has some problems, so a new asymmetric catalytic hydrogenation method with high efficiency, high stereoselectivity and wide substrate applicability is urgently needed to be found.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for preparing (R) - α -aryl alanine ester derivatives, which is suitable for industrial production and can conveniently prepare kilogram-level (R) - α -aryl alanine ester derivatives with high purity and high enantioselectivity.
The technical scheme adopted by the invention is as follows:
a method for preparing an (R) -alpha-aryl alanine ester derivative, comprising the steps of:
1) under argon atmosphere, metal Rh complex and chiral ligand L*Adding the obtained product into a solvent A to react for 0.5 to 6 hours to obtain a metal Rh complex and a chiral ligand L*Coordination bound catalysts [ Rh]/L*；
2) Adding alpha-dehydro aryl alanine ester derivative shown as formula (2) and the prepared catalyst [ Rh ] into an autoclave]/L*And solvent B, carrying out asymmetric hydrogenation reaction at 10-80 ℃ and under the hydrogen pressure of 0.1-6.0 MPa, and carrying out reactionAfter reacting for 1-24 hours, carrying out reduced pressure distillation to recover the solvent B, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, and carrying out reduced pressure distillation to recover the solvent to obtain the (R) -alpha-aryl alanine ester derivative shown in the formula (1);
the specific reaction route is as follows:
in the formulas (1) and (2), the aryl Ar is selected from phenyl, heterocyclic group, naphthyl or substituted phenyl, and the substituent in the substituted phenyl is C1-6 alkyl, C1-6 alkoxy or halogen, nitro; r is1Selected from acetyl, benzyloxycarbonyl, tert-butoxycarbonyl; r2Selected from C1-6 alkyl;
further, the chiral ligand L*The chemical structural formula of (A) is shown as the general formula (L):
in the general formula (L): r3And R4Each independently substituted or unsubstituted, when substituted, the substituent R3And a substituent R4Each independently selected from halogen, aryl, C1-C6 alkyl.
Further, a chiral ligand L represented by the general formula (L)*The chemical structural formula of (A) is shown in any one of formulas (L-1) to (L-4):
further, the metal Rh complex is [ Rh (C)2H4)2Cl]2、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、[Rh(NBD)2]BF4、[Rh(COD)2]X、Rh(ethylene)2(acac)、[Rh(acac)(CO)]2、[Rh(C2H4)2Cl]2、RhCl(PPh3)3、[Rh(CO)2C1]2、Rh(arene)X2(diphosphine)、Rh(aryl group)X2、Rh(COD)(COT)、Rh(COD)(COT)X、Rh(COD)(methallyl)2、RhX2(diphosphine)、RhCl2(COD)、RhX2(cymene)、Rh(arylgroup)X2(PPh3)3、Rh(methallyl)2(diphosphine) and Rh (aryl group) X2(diphosphine) wherein aryl is aryl and X is BF4 -、OTf-、ClO4 -、SbF6 -、PF6 -、CF3SO3 -Or B (Y)4 -Y is bis (trifluoromethyl) benzene or fluorobenzene.
Further, in step 2), catalyst [ Rh ] is added]/L*The molar ratio of the alpha-dehydroaryl alanine ester derivative to the alpha-dehydroaryl alanine ester derivative is 1: 100-1: 100000.
Further, in step 1), a catalyst [ Rh ] was prepared]/L*The temperature of the reaction is 10-40 ℃, and the reaction time is 0.5-3 hours.
Further, in the step 2), the temperature for carrying out the asymmetric hydrogenation reaction is 10-60 ℃, the hydrogen pressure is 0.1-3.0 MPa, and the reaction time is 4-24 hours.
Further, the concentration of the α -dehydroarylalanine ester derivative represented by the formula (2) in the solvent B is from 0.05mol/L to 5.0 mol/L.
Further, the solvent A in the step 1) and the solvent B in the step 2) are respectively and independently selected from one or a mixture of more than two of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol and tert-butanol, and the solvent A and the solvent B can be the same.
By adopting the technology, compared with the prior art, the invention has the following characteristics:
the invention develops a catalyst consisting of chiral phosphine-spiroindane phosphoramidite bidentate ligand containing ferrocene skeleton and metal complex, and the catalyst is easy to prepare; the catalyst prepared by the invention does not need to be specially purified and can be directly used for the reaction of preparing the (R) -alpha-aryl alanine ester derivative by catalytic hydrogenation; compared with the existing asymmetric hydrogenation method, the method has the advantages of low catalyst dosage (TON is as high as 100000), excellent enantioselectivity (ee value is generally more than 99%), wide substrate applicability and the like, and has the advantages of easily available raw materials, simple operation, mild reaction conditions, easy industrialization, accordance with the requirements of green chemistry, great implementation value and social and economic benefits.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.94mmol), wherein the yield is as follows: 99%, purity: 99% and an ee value of 99.9%.
Example 2: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(47.3mg, 55.0. mu. mol) and metal complex [ Rh (COD)2]BF4Adding the mixture (20.3mg,50.0 mu mol) into a reaction bottle, adding dichloromethane (30mL) under the argon atmosphere, and reacting at 25 ℃ for 0.5h to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1kg, 5.0mol), the catalyst prepared in the step 1) and dichloromethane (3.0L) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12 hours, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.07kg,4.81mol), wherein the yield is as follows: 96%, purity: 98% and an ee value of 99.0%.
Example 3: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, filling hydrogen to 3.0MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.07g,4.85mmol), wherein the yield is as follows: 97%, purity: 98% and an ee value of 98.7%.
Example 4: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 μmol) is added into a reaction bottle, tetrahydrofuran (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and tetrahydrofuran (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.08g,4.89mmol), wherein the yield is as follows: 98%, purity: 99% and an ee value of 99.1%.
Example 5: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 mu mol) is added into a reaction bottle, toluene (5mL) is added under the argon atmosphere, and the reaction lasts for 0.5h at 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and toluene (15mL) into a reaction bottle, replacing three times with argon and hydrogen respectively, keeping the hydrogen atmosphere at 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting the organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06g,4.80mmol), wherein the yield is as follows: 96%, purity: 97% and ee value 96.2%.
Example 6: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 mu mol) is added into a reaction bottle, methanol (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and methanol (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.94mmol), wherein the yield is as follows: 99%, purity: 99% and an ee value of 99.3%.
Example 7: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligandsL-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, isopropanol (5mL) is added under the atmosphere of argon, and the mixture reacts for 0.5h at 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and isopropanol (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, maintaining a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.08g,4.89mmol), wherein the yield is as follows: 98%, purity: 98% and an ee value of 97.9%.
Example 8: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 mu mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction lasts for 0.5h at 25 ℃, thus obtaining the catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 10 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.04g,4.69mmol), wherein the yield is as follows: 94%, purity: 96% and an ee value of 99.9%.
Example 9: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) and dichloromethane (15mL) into a reaction bottle, replacing with argon and hydrogen for three times respectively, keeping the hydrogen atmosphere at 0.1MPa, reacting at 40 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting the organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.08g,4.90mmol), wherein the yield is as follows: 98%, purity: 98% and an ee value of 99.0%.
Example 10: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and metal complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 60 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06g,4.80mmol), wherein the yield is as follows: 96%, purity: 97% and ee value 96.1%.
Example 11: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the mixture reacts for 0.5h at the temperature of 10 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -N-acetylphenylalanine methyl ester (1.06g,4.80mmol), wherein the yield is as follows: 96%, purity: 98% and an ee value of 98.3%.
Example 12: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 40 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.92mmol), wherein the yield is as follows: 98%, purity: 99% and an ee value of 99.0%.
Example 13: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) was reacted with a metal complex [ Rh (NBD) ]2]BF4(1.87mg,5.0 mu mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.94mmol), wherein the yield is as follows: 97%, purity: 98% and an ee value of 97.3%.
Example 14: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]OTf (2.34mg, 5.0. mu. mol) plusPutting the mixture into a reaction bottle, adding dichloromethane (5mL) under the argon atmosphere, and reacting for 0.5h at 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in step 1) and dichloromethane (15mL) into a reaction bottle, replacing with argon and hydrogen for three times respectively, keeping the hydrogen atmosphere at 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting the organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06g,4.80mmol), wherein the yield is as follows: 96%, purity: 98% and an ee value of 96.8%.
Example 15: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) was reacted with metal complex [ Rh (NBD) Cl]2(1.15mg, 2.5. mu. mol) into a reaction bottle, adding dichloromethane (5mL) under argon atmosphere, and reacting at 25 ℃ for 0.5h to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -N-acetylphenylalanine methyl ester (1.04g,4.71mmol), wherein the yield is as follows: 94%, purity: 98% and ee value 91.2%.
Example 16: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) was reacted with a metal complex [ Rh (C)2H4)2Cl]2(0.97mg, 2.5. mu. mol) into a reaction bottle, adding dichloromethane (5mL) under argon atmosphere, and reacting at 25 ℃ for 0.5h to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.05g,4.75mmol), wherein the yield is as follows: 95%, purity: 97% and an ee value of 92.2%.
Example 17: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-2(5.28mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.04g,4.70mmol), wherein the yield is as follows: 94%, purity: 97% and an ee value of 92.9%.
Example 18: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-3(4.05mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.04g,4.68mmol), wherein the yield is as follows: 94%, purity: 96% and an ee value of 92.1%.
Example 19: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-4(3.89mg, 5.5. mu. mol) and metal complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.91mmol), wherein the yield is as follows: 98%, purity: 99% and ee value 98.3%.
Example 20: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg,5.0 mu mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction lasts for 0.5h at 25 ℃, thus obtaining the catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (100mL) into a high-pressure reaction kettle, sealing the reaction kettle, replacing the reaction kettle with argon and hydrogen for three times respectively, filling hydrogen to 1.0MPa, reacting at 25 ℃ for 12 hours, after the reaction is finished, recovering the solvent by reduced pressure distillation, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, recovering the solvent by reduced pressure distillation, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.09g,4.91mmol), wherein the yield is as follows: 98%, purity 98%, ee value 98.3%.
Example 21: preparation of (R) -alpha-N-acetylphenylalanine methyl ester
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) was added to the reaction flask under an argon atmosphereAdding dichloromethane (5mL) to react for 0.5h at 25 ℃ to prepare a catalyst;
2) adding (Z) -N-acetyl-alpha-dehydrophenylalanine methyl ester (1.1g, 5.0mmol), the catalyst prepared in the step 1) and dichloromethane (1mL) into a high-pressure reaction kettle, sealing the reaction kettle, replacing the reaction kettle with argon and hydrogen for three times respectively, filling hydrogen to 1.0MPa, reacting at 25 ℃ for 12 hours, after the reaction is finished, recovering the solvent by reduced pressure distillation, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, recovering the solvent by reduced pressure distillation, and obtaining (R) -alpha-N-acetylphenylalanine methyl ester (1.06g,4.79mmol), wherein the yield is as follows: 96%, purity 97%, ee value 97.2%.
Examples 22 to 40: preparation of (R) -alpha-aryl alanine ester derivatives
1) Chiral ligand L-1(4.73mg, 5.5. mu. mol) and Metal Complex [ Rh (COD)2]BF4(2.03mg, 5.0. mu. mol) is added into a reaction bottle, dichloromethane (5mL) is added under the argon atmosphere, and the reaction is carried out for 0.5h at the temperature of 25 ℃ to obtain a catalyst;
2) adding (Z) -alpha-dehydro-aryl alanine ester derivative (5.0mmol), the catalyst prepared in the step 1) and dichloromethane (15mL) into a reaction bottle, respectively replacing with argon and hydrogen for three times, keeping a hydrogen atmosphere of 0.1MPa, reacting at 25 ℃ for 12h, after the reaction is finished, carrying out reduced pressure distillation to recover the solvent, adding appropriate amount of water, extracting with ethyl acetate, collecting an organic phase, drying, carrying out reduced pressure distillation to recover the solvent, and obtaining the (R) -alpha-aryl alanine ester derivative, wherein the yield, the purity and the ee value of the product are shown in Table 1.
The reaction formula is as follows:
TABLE 1 Experimental results for examples 22 to 40
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (9)
1. A method for preparing an (R) -alpha-aryl alanine ester derivative, which is characterized by comprising the following steps:
1) under argon atmosphere, metal Rh complex and chiral ligand L*Adding the obtained product into a solvent A to react for 0.5-6 hours to obtain a metal Rh complex and a chiral ligand L*Coordination bound catalysts [ Rh]/L*；
2) Adding alpha-dehydro aryl alanine ester derivative shown as formula (2) and the prepared catalyst [ Rh ] into an autoclave]/L*And a solvent B, carrying out asymmetric hydrogenation reaction at 10-80 ℃ and under the hydrogen pressure of 0.1-6.0 MPa, reacting for 1-24 hours, carrying out reduced pressure distillation to recover the solvent B, adding a proper amount of water, extracting with ethyl acetate, collecting an organic phase, drying, and carrying out reduced pressure distillation to recover the solvent to obtain the (R) -alpha-aryl alanine ester derivative shown in the formula (1);
the specific reaction route is as follows:
in the formulas (1) and (2), the aryl Ar is selected from phenyl, heterocyclic group, naphthyl or substituted phenyl, and the substituent in the substituted phenyl is C1-6 alkyl, C1-6 alkoxy or halogen, nitro; r1Selected from acetyl, benzyloxycarbonyl, tert-butoxycarbonyl; r2Selected from C1-6 alkyl.
2. The method for preparing (R) - α -arylalanine ester derivatives according to claim 1, wherein the chiral ligand L*The chemical structural formula of (A) is shown as the general formula (L):
in the general formula (L): r3And R4Each independently substituted or unsubstituted, when substituted, the substituent R3And a substituent R4Each independently selected from halogen, aryl, C1-C6 alkyl.
3. The method for preparing (R) - α -arylalanine ester derivatives according to claim 2, wherein the chiral ligand L is represented by the formula (L)*The chemical structural formula of (A) is shown as any one of the formulas (L-1) to (L-4):
4. the method for preparing (R) - α -arylalanine ester derivative according to claim 1, wherein said metal Rh complex is [ Rh (C)2H4)2Cl]2、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、[Rh(NBD)2]BF4、[Rh(COD)2]X、Rh(ethylene)2(acac)、[Rh(acac)(CO)]2、[Rh(C2H4)2Cl]2、RhCl(PPh3)3、[Rh(CO)2C1]2、Rh(arene)X2(diphosphine)、Rh(aryl group)X2、Rh(COD)(COT)、Rh(COD)(COT)X、Rh(COD)(methallyl)2、RhX2(diphosphine)、RhCl2(COD)、RhX2(cymene)、Rh(arylgroup)X2(PPh3)3、Rh(methallyl)2(diphosphine) and Rh (aryl group) X2(diphosphine) wherein aryl is aryl and X is BF4 -、OTf-、ClO4 -、SbF6 -、PF6 -、CF3SO3 -And B (Y)4 -Y is bis (trifluoromethyl) benzene or fluorobenzene.
5. The method for preparing (R) - α -arylalanine ester derivative according to claim 1, wherein in the step 2), the catalyst [ Rh ] is added]/L*The molar ratio of the alpha-dehydroaryl alanine ester derivative to the alpha-dehydroaryl alanine ester derivative is 1: 100-1: 100000.
6. The method for preparing (R) - α -arylalanine ester derivative according to claim 1, wherein in the step 1), the catalyst [ Rh ] is prepared]/L*The temperature of the reaction is 10-40 ℃, and the reaction time is 0.5-3 hours.
7. The method for preparing an (R) - α -arylalanine ester derivative according to claim 1, wherein the asymmetric hydrogenation is carried out at 10-60 ℃ under a hydrogen pressure of 0.1-3.0 MPa for 4-24 hours in step 2).
8. The process for producing an (R) - α -arylalanine ester derivative according to claim 1, wherein the concentration of the α -dehydroarylalanine ester derivative represented by the formula (2) in the solvent B is from 0.05mol/L to 5.0 mol/L.
9. The method for preparing an (R) - α -arylalanine ester derivative according to claim 1, wherein the solvent A in the step 1) and the solvent B in the step 2) are independently selected from one or more mixed solvents of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol and tert-butanol.
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